Mechanism and treatment strategies of immune checkpoint inhibitors related biliary type hepatotoxicity / 中国肿瘤生物治疗杂志

@#肿瘤免疫检查点抑制剂（ICI）治疗近年来因疗效显著而备受瞩目。ICI引起的免疫介导肝毒性（IMH）是一类较常见的免疫相关不良反应（irAE），但IMH中的一种亚分型，胆管型IMH（BIMH），却是一种少见的、对其认知极不充分、缺乏诊疗规范的irAE，存在临床隐患。BIMH以胆管酶显著升高、高胆红素血症为临床特点，组织病理学表现为胆管炎症、胆管损伤和消失。胆汁淤积阶段的BIMH对于免疫抑制治疗反应不佳，预后差。提高对BIMH的认识，早期诊断和干预是提高BIMH预后的关键。对BIMH流行病学特征、临床特征、组织病理学特点和发生机制及BIMH全程管理中存在之问题等认识的不断提高，有助于提出针对BIMH的有效诊疗策略。

Practice of precision oncology: targeting the tumor immune microenvironment / 中国肿瘤生物治疗杂志

@#近年来，肿瘤免疫治疗技术的发展为拓宽精准肿瘤医学领域做出了巨大贡献。免疫微环境是影响免疫治疗效果的重要因素，其在肿瘤进展和动员抗肿瘤免疫方面都有不可忽视的作用。针对肿瘤免疫微环境的免疫性放疗、免疫检查点抑制剂、肿瘤疫苗和免疫细胞治疗等手段已在临床研究中取得了很多成果，但其临床疗效仍有待提高。本文在介绍肿瘤免疫微环境的组成和特征的基础上，从临床应用的角度阐述针对目前靶向肿瘤免疫微环境的治疗手段可行的优化策略。

T lymphocyte homing: a critical factor of adoptive cell therapy for solid tumors / 中国肿瘤生物治疗杂志

@#[Abstract] In recent years, tumor immunotherapy has developed rapidly, among which T-cell-based adoptive cell therapy has achieved certain clinical effect and become one of the most potential immunotherapeutics. T cell infiltration mainly includes rolling, adhesion, extravasation and chemotaxis etc. However, there are physical barriers, chemokine mismatch, vascular abnormalities, immunosuppressive microenvironment and other factors that limit the efficacy of adoptive cell therapy. The homing ability of T cells can be further improved by optimizing the chemokine receptor on the cell surface, inserting targeted peptide, improving the way of administration, and adopting combined treatment of radiotherapy, immune checkpoint blocker, tumor vaccine and bispecific antibody, etc. This review mainly summarizes the process of T cell infiltration, the influencing factors of T cell targeting tumor site and the relevant treatment strategies, as well as gives a prospection for future research.

Clinical significance of CEA mRNA expression in peritoneal lavage fluid for patients with gastric cancer after radical surgery / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate the expression and clinical significance of CEAmRNAin peritoneal lavage fluid for patients with gastric cancer after radical surgery. Methods: The clinical data of 139 gastric cancer patients, who underwent peritoneal lavage CEA mRNA detection after radical resection in the Comprehensive Cancer Centre of Drum Tower Hospital from January 2013 to December 2017 were retrospectively analyzed. Routine post-operative follow-up was conducted in all patients. The expression of CEA mRNA in peritoneal lavage fluid after radical resection of 139 gastric cancer patients was detected by RT-PCR. Chi-square test analysis was used to study the relationship between the expression of CEA mRNA in peritoneal lavage fluid and basic clinical features, histopathological data, hematological indicators and the recurrence pattern of GC patients. Logistic univariate and multivariate regression analyses were used to screen the influential factors affecting CEA mRNA expression. Results: CEA mRNA was positive in 44 (31.7%) of 139 patients. Analysis showed that there was no significant correlation between CEA mRNA expression and sex, age, pathological grade, Lauren type, HER2, EGFR, VEGFR and Ki67 (all P>0.05), but there was significant correlation between CEA mRNA expression and pathological type, vascular invasion, local invasion depth, lymph node metastasis and clinical AJCC stage (all P<0.05). The peritoneal recurrence rate of patients with positive CEA mRNA expression was significantly higher than that of patients with negative expression (P=0.012). Logistic univariate regression analysis showed that signet ring cell carcinoma (P=0.04, HR=2.810， 95% CI: 1.050-7.520), T stage (P=0.016，HR=6.329, 95% CI: 1.417-28.264), N stage (P=0.022，HR=3.068，95% CI: 1.172-8.027), AJCC stage (P=0.016，HR= 3.971, 95% CI: 1.295-12.173), nerve invasion (P=0.002, HR=6.738, 95% CI: 1.995-22.757) and vascular invasion (P<0.001, HR= 16.36, 95% CI: 3.85-69.512) were risk factors for positive CEA mRNA expression in peritoneal lavage fluid of patients with gastric cancer. Logistic multivariate regression analysis showed that vascular invasion (P<0.001, HR=21.314，95% CI: 4.21-107.907) was an independent risk factor for positive CEAexpression in peritoneal lavage fluid of gastric cancer patients. Conclusion: Gastric cancer patients with positive CEA mRNA in peritoneal lavage fluid have higher risk of peritoneal recurrence or metastasis and poorer prognosis. So, more aggressive anti-tumor treatments including local abdominal cavity treatment should be considered.

In situ vaccine: new ideas for tumor immunotherapy / 中国肿瘤生物治疗杂志

@#肿瘤免疫治疗的新策略发展迅速，已经成为肿瘤治疗最受瞩目的领域。关于如何实现最理想抗肿瘤免疫效果，可采 用“被动”免疫疗法如过继性细胞疗法、基因工程T细胞等直接攻击肿瘤细胞，也可采用“主动”免疫疗法如细胞因子、肿瘤疫苗、 免疫检查点抑制剂等调节并激活免疫系统。原位疫苗以局部瘤内注射的方式， 将“主动”和“被动”免疫科学地结合起来，在直接 抑制肿瘤细胞的同时深度调节和触发机体免疫系统，形成免疫启动-免疫效应-肿瘤细胞死亡-抗原释放导致免疫再启动-免疫再 效应的反复循环，最大限度地发挥抗肿瘤免疫效果。本文就原位疫苗的具体策略、临床前研究和临床试验的进展，以及原位疫苗 的优势、存在问题和应对策略等展开讨论。

Preparation of human peripheral blood T lymphocytes with TIM3 gene knockout and its anti-tumor efficacy / 中国肿瘤生物治疗杂志

@#Objective: To prepare human peripheral blood T lymphocytes with TIM3 (T cell immunologlobulin and mucin-3) gene knockout by using CRISPR-Cas9 gene editing technique and plasmid electrotransfection system, and to discuss whether the knockout of TIM3 gene could enhance the immune response and anti-tumor efficacy of T cells. Methods: Double plasmids hTIM3 sgRNA/Cas9 were transfected into human peripheral blood T lymphocytes of EBV positive gastric cancer patients by using electrotransfection system. The transfection efficiency was examined 24 h later by flow cytometry and fluorescence microscope. The proliferation activity of the T cells after gene knockout was observed during in vitro culture, and the knockout efficiency and phenotypes of the modified T cells were evaluated by flow cytometry. Furthermore, tumor antigen peptide was used to activate T cells, and the level of modified T cells secreting cytokines and its cytotoxicity against gastric cancer AGS-EBV cells were evaluated. Results: Electrotransfection system could successfully transfect hTIM3 sgRNA/Cas9 double plasmids into human peripheral blood T lymphocytes with an average transfection efficiency of (41.5±3.6)%, and the gene knockout efficiency fluctuated between 40.0% and 50.0% (all P<0.01). The proliferation of the modified T cells was not significantly changed in the TIM3 gene knockout group even after the prolonged co-culturing with tumor antigenic peptide;and for the activated molecules, only HLA-DR exhibited significant elevation as compared with control group (P<0.05). Remarkably, T cells with TIM3 gene knockout showed significantly elevated secretion of TNF-α and IFN-γ (P<0.01 or P<0.05), as well as obviously enhanced in vitro cytotoxicity against gastric cancer AGS-EBV cells (P<0.05). Conclusion: It’s simple and feasible of CRISPR-Cas9 gene editing technique and plasmid electrotransfection system to prepare T lymphocytes with engineered TIM3 gene knockout. The expression level of TIM3 was down-regulated in in vitro culture. More importantly, the modified T cells performed superior immune response and cytotoxicity, which may provide a new idea for gene engineering cell immunotherapy.

Current situation and challenges of T cell receptor-engineered T cells in anti-tumor therapy / 中国肿瘤生物治疗杂志

@#T cell receptor-engineered T cell (TCR-T) therapy is one of the hotspots in the field of cancer immunotherapy. Considerable achievements have been made since the first successful clinical trial in 2006. However, problems still remain in cytotoxicity, safety and persistence of TCR-T therapy despite the rapid development. Improving the immunosuppressive tumor microenvironment and enhancingchemotaxis, infiltration as well as activation of TCR-T cell will be the key to improve its anti-tumor effect. Neoantigens, which are highly tumor-specific and immunogenic,are the basis for safe and effective treatment and individualized cancer immunotherapy. Besides, infusion of less differentiated T cell subsets is also a reliable way to generate a long-lasting immune response. Here, combing with current research progress, we offer our perspectives on the current situation and challenges of TCR-T from the three aspects above.

Molecular classification of gastric cancer and individualized immunotherapy / 中国肿瘤生物治疗杂志

@#Gastric cancer (GC) is one of the malignant tumors with the highest morbidity and mortality in China, and conventional therapies such as surgery, chemotherapy and radiotherapy have limited curative effect on it. GC is highly heterogeneous. With the research on GC deepening into a molecular level and the rapid development of immunotherapy, individualized immunotherapy has become the most promising technology in the field of GC therapy. Several molecular classifications have been put forward in recent years, accurately as well as comprehensively depicting the genomic and molecular characteristics of GC. Moreover, molecular classifications also provided molecular immunological information of GC, which gave implications for the screening of benefit population and treatment decision-making. Based on the several existing GC molecular classifications, this review discussed the guiding significance of molecular classifications on the development and application of GC individualized immunotherapy.